Deuterium-labeled and tritium-labeled organic and organometallic compounds are used widely in spectroscopic experiments and in studies aimed at the elucidation of chemical structure and reaction mechanisms. These materials are expensive because they must be prepared by H/D exchange from unlabeled starting materials, often in multi-sequence procedures that require a more common compound to serve as a source of deuterium that can be transferred into the by molecule of interest. Using classical methods it is usually easiest to exchange deuterium with so-called xe2x80x9cactivatedxe2x80x9d protons (e.g., protons that are acidic, or susceptible to electrophilic exchange using strong acids); exchange with xe2x80x9cunactivatedxe2x80x9d protons is much more difficult. As a result, many deuterium-labeled compounds are either expensive or not available commercially. The present invention relates to a process for the preparation of a deuterated and/or tritiated compound which is useful as a raw material for pharmaceuticals, agricultural chemical, functional materials, analytical tracers and similar uses. When reference is made to deuterium and deuteration it is intended to include also tritium and tritiation, or a mixture of deuterium and tritium.
To make deuterium-labeled and tritium labeled organic and organometallic materials less expensively and more readily available, the chemical community requires a universal (preferably catalytic) method that would allow H/D exchange from an inexpensive deuterium and tritium source into a wide range of proton-containing compounds. The deuterium and tritium source that fits these criteria ideally is D2O and T2O, due to their low cost and low toxicity.
U.S. Pat. No. 3,510,519 to Frejaville et al. relates to the preparation of deuterated compounds by contacting and reacting under non-turbulent countercurrent flow conditions two compounds wherein one of the compounds is in liquid form and the other is in gaseous form. Frejaville et al. rely on a greatly elongated uncatalyzed reaction zone to achieve H-D exchange.
U.S. Pat. No. 3,989,705 describes a process for the deutriation of organic substrates by hydrogen substitution using a strong acid and high temperatures.
U.S. Pat. No. 3,900,557 to Strathdee describes a catalyst comprising a transition metal coordination complex anchored on a cross-linked polystyrene. The anchored catalyst is useful for promoting H-D exchange between deuterated forms of hydrogen-containing gas stuns and liquid water or alcohols.
U.S. Pat. No. 4,421,865 describes a process for deuterating compounds using a porous ion exchange resin.
U.S. Pat. No. 5,149,820 describes deuterated aromatic aldehydes used for anti-cancer drugs.
U.S. Pat. No. 5,186,868 describes methods for tritium labeling comprising reacting an organic solvented solution of alkali metal alkyl with a tritium gas in the presence of an alkyl tertiary amine.
U.S. Pat. No. 5,733,984 describes a press for the preparation of a deuterated compound comprising treating an organic compound in heavy water under high-temperature and high-pressure conditions not less than the subcritical temperature and subcritical pressure.
U.S. Pat. No. 5,830,763 describes a process for producing a deuterated compound comprising heating a deuterium oxide solution at a specific pH and at a temperature and pressure so that a supercitical reaction mass forms.
The above U.S. Patents are hereby incorporated by reference in their entirety.
In an important step toward the solution of the problems described in the paragraphs above, the inventors have surprisingly discovered a class of transition metal catalysts that catalyze the exchange of deuterium from D2O into a wide range of organic and organometallic compounds that are otherwise difficult to deuterate. Exchange occurs with both traditionally xe2x80x9cactivatedxe2x80x9d and xe2x80x9cunactivatedxe2x80x9d hydrogens. The most active catalysts of this invention have been found to be [Cp*(PMe3)IrH3][OTf] and Cp*(PMe3)IrCl2, but this invention contemplates that any organometallic catalyst having the general formula described herein below is suitable. The latter catalyst is air stable, and is prepared in two high-yielding steps from commercially available IrCl3xe2x80x943H2O.
The preparative advantages of these catalysts include their facile removal from products and their stability toward air and water. In contrast to related catalysts based on platinum that have been reported to act similarly, the use of strongly acidic conditions is not necessary, and their activity is higher than that of previously reported rhodium and iridium complexes. The H/D exchange according to the instant invention occurs under moderate conditions. Water typically participates in H/D exchange only with activated hydrogens, which would lead one to believe that the instant invention would not work efficiently; surprisingly the inventors have found two catalyst compositions that do work. Water often causes organometallic compounds to decompose, which would also lead one to believe that the instant invention would not work efficiently. Again however, the inventors have surprisingly found catalyst compositions that will work in an aqueous environment.